Summary: Researchers report genes that exhibit the greatest left-right differences in embryos are also implicated in an increased risk of developing schizophrenia.
Source: Max Planck Institute for Psycholinguistics.
Our nervous systems have left-right differences that are important for correct functioning. Handedness is probably the best known asymmetry arising from the development of the nervous system. This is observed very early on: embryos of eight weeks already tend to move their right arms more often than their left arms. At this ‘age’ signals are not sent from the brain to the arms yet, but only from the spinal cord. A few weeks later, left-right differences also become visible in the shape and size of the premature brain.
TA team of scientists from the Netherlands, the UK and China searched for genes that contribute to left-right differences in the nervous system, in the period between four and eight weeks after fertilization. The genetic analysis showed that the left and right sides of the spinal cord develop at different paces.
The left side of the spinal cord matures slightly faster than the right side. Sets of key genes that control growth and maturity were found to reach a more advanced profile of activity on the left side than the right. In the hindbrain, an area which is the predecessor for some adult parts of the brain, this was the other way around.
“This seems logical, since many nerve fibers cross over from one side to the other at the boundary between the hindbrain and spinal cord,” says Carolien de Kovel, lead author of the study and researcher at the Max Plank Institute for Psycholinguistics (MPI). “How exactly this left-right genetic difference in the spinal cord leads to right-handedness is, however, not yet clear.”
Clyde Francks, head of the MPI research group ‘Brain and behavioral asymmetries’ and Research Fellow at the Donders Institute at the Radboud University, explains, “We think that these very early left-right differences in the spinal cord may act to trigger some of the later asymmetries of the brain, such as the eventual dominance of the left hemisphere for language functions in most adults’.
Asymmetry and schizophrenia
“Around 85% of humans are right-handed; it seems the standard in human development,” De Kovel adds, “but genetic and environmental factors may provide alternative paths of development, such as left-handedness or two-handedness. Interestingly, disturbances in such asymmetries seem to be more common in people with psychiatric conditions such as schizophrenia.”
Hence, De Kovel and her colleagues also compared the results of their study with genetic factors that influence the risk of schizophrenia. It was found that genes which exhibit the largest left-right differences in the embryos also tended to be involved in the risk of schizophrenia. “The findings do not prove directly that these genes cause schizophrenia by their actions in the spinal cord, because the same genes are also active in the grown up brain. However this does provide us with clues on which we can base further research,” De Kovel explains.
Funding: The research was funded by an Open Programme grant from the Netherlands Organization for Scientific Research, and is published in the journal Biological Psychiatry.
Source: Charlotte Horn – Max Planck Institute for Psycholinguistics
Image Source: NeuroscienceNews.com image is credited to Max Planck Institute for Psycholinguistics.
Original Research: Abstract for “Left-right asymmetry of maturation rates in human embryonic neural development” by Carolien G.F. de Kovel, Steven Lisgo, Guy Karlebach, Jia Ju, Gang Cheng, Simon E. Fisher, and Clyde Francks in Biological Psychiatry. Published online February 1 2017 doi:10.1016/j.biopsych.2017.01.016
Left-right asymmetry of maturation rates in human embryonic neural development
Left-right asymmetry is a fundamental organizing feature of the human brain, and neuro-psychiatric disorders such as schizophrenia sometimes involve alterations of brain asymmetry. As early as 8 weeks post conception, the majority of human fetuses move their right arms more than their left arms, but because nerve fibre tracts are still descending from the forebrain at this stage, spinal-muscular asymmetries are likely to play an important developmental role.
We used RNA sequencing to measure gene expression levels in the left and right spinal cords, and left and right hindbrains, of 18 post-mortem human embryos aged 4-8 weeks post conception. Genes showing embryonic lateralization were tested for an enrichment of signals in genome-wide association data for schizophrenia.
The left side of the embryonic spinal cord was found to mature faster than the right side. Both sides transitioned from transcriptional profiles associated with cell division and proliferation at earlier stages, to neuronal differentiation and function at later stages, but the two sides were not in synchrony (p = 2.2 E-161). The hindbrain showed a left-right mirrored pattern compared to the spinal cord, consistent with the well-known crossing over of function between these two structures. Genes that showed lateralization in the embryonic spinal cord were enriched for association signals with schizophrenia (p = 4.3 E-05).
These are the earliest-stage left-right differences of human neural development ever reported. Disruption of the lateralised developmental programme may play a role in the genetic susceptibility to schizophrenia.
“Left-right asymmetry of maturation rates in human embryonic neural development” by Carolien G.F. de Kovel, Steven Lisgo, Guy Karlebach, Jia Ju, Gang Cheng, Simon E. Fisher, and Clyde Francks in Biological Psychiatry. Published online February 1 2017 doi:10.1016/j.biopsych.2017.01.016